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Pancreatic cancer (PCa) is the 4th leading cause of cancer fatality in the United States and has the lowest 5-year survival rate of any major cancer (ACS). More than 70% of patients die within the first year after being diagnosed. By year 2020, it is anticipated that PCa will move to the 2nd leading cause of cancer death. At the time of diagnosis, over 52% of the patients have distant disease and 26% have regional spread. Only ˜15% of patients diagnosed with pancreatic adenocarcinoma can have their tumors surgically removed. Lack of early diagnosis, complex biology of the disease, and limited treatment options contribute to making PCa a major killer.
Virtually all pancreatic tumors are adenocarcinomas of which the vast majority expresses a mutant K-Ras. Over two decades of PCa research suggest a model for disease progression where early, low-grade pancreatic intraepithelial neoplasia (PanIN), is associated with KRAS2 mutations and telomere shortening. Intermediate and late stages of the disease are characterized by loss of p16/CDKN2A, SMAD4, p53, and BRCA2 respectively. Additionally, a massive effort to sequence the genomes of 24 independently derived advanced pancreatic adenocarcinomas revealed a remarkably complex pattern of genetic mutations. On average, there were 63 genetic mutations in PCa. The majority (67%) of the mutations could be classified into 12 partially overlapping cellular signaling pathways.
PCas are notoriously insensitive to the backbone of cancer chemo- and radiation therapy, all of which target processes essential for the integrity of the genome. Understanding the mechanisms of chemoresistance of PCa will provide new targets that enhance cell killing.